# US 5,344,927 A · Tetrahydrobenzimidazole derivatives and pharmaceutical compositions containing same > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,344,927 A - Document ID: US5344927A - Status: Granted - Kind: A - Application number: 08/039,633 - Filed: 1993-03-30 - Granted: 1994-09-06 - Earliest claimed: 1989-02-02 - Assignees: Yamanouchi Pharmaceutical Co., Ltd. - Inventors: Mitsuaki Ohta; Tokuo Koide; Takeshi Suzuki; Akira Matsuhisa; Keiji Miyata; Junya Ohmori; Isao Yanagisawa - Web page: https://patentgrep.com/patent/US5344927A ## CPC - C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms - C07D 235/26: Oxygen atoms - C07D 235/30: Nitrogen atoms not forming part of a nitro radical - C07D 401/12: linked by a chain containing hetero atoms as chain links - C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms - C07D 403/12: linked by a chain containing hetero atoms as chain links - C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms - C07D 409/12: linked by a chain containing hetero atoms as chain links - C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms - C07D 417/12: linked by a chain containing hetero atoms as chain links - C07D 471/04: Ortho-condensed systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract A tetrahydrobenzimidazole derivative represented by formula (I): ##STR1## wherein Het represents a heterocyclic group which may be substituted with 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl-lower alkyl group, an aralkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, a lower alkoxycarbonyl group, and a halogen atom; and X represents a single bond or --NH-- which is bonded to the carbon atom or nitrogen atom of the heterocyclic ring, or a pharmaceutically acceptable salt thereof. The compound of formula (I) and a salt thereof exhibits antagonism against 5-HT.sub.3 receptor. ## Claims ### Claim 1 A tetrahydrobenzimidazole derivative represented by formula (I): ##STR60## wherein Het represents a member selected from the group consisting of pyrollidine, piperidine, piperazine, morpholine, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, 4H-cyclopentathiazole, indole, isoindole, 2,3-dihydroindole (indoline), isoindoline, hydroxyindole, indazole, indolizine, benzothiophene, benzofuran, benzothiazole, benzimidazole, benzoxazole, 4,5,6,7-tetrahydrobenzothiophene, 2,3-dihydrobenzimidazol-2-one, quinoline, isoquinoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 1,4-benzoxazine, phenothiazine, carbazole and .beta.-carboline, and wherein Het may be substituted with 1 to 3 substituents selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl-lower alkyl, aralkyl, lower alkoxy, nitro, hydroxyl, lower alkoxycarbonyl, and halo; and X represents a single bond or --NH-- which is bonded to the carbon atom or nitrogen atom of the heterocyclic ring of said Het, or a pharmaceutically acceptable salt thereof. ### Claim 2 (depends on 1) The derivative as claimed in claim 1 wherein X represents a single bond. ### Claim 3 (depends on 1) The derivative as claimed in claim 1 wherein X represents a single bond connected to a nitrogen atom of the Het group. ### Claim 4 (depends on 1) The derivative as claimed in claim 1 wherein X represents --NH--. ### Claim 5 (depends on 1) The derivative as claimed in claim 1 wherein Het is pyrrolidinyl. ### Claim 6 (depends on 1) The derivative as claimed in claim 1 wherein Het is 1,2,3,4-tetrahydroisoquinolinyl. ### Claim 7 (depends on 1) The derivative as claimed in claim 1 wherein Het is 2,3-dihydrobenzimidazol-2-one-yl. ### Claim 8 (depends on 1) The derivative as claimed in claim 1 wherein Het is N-(2-benzothiazolyl). ### Claim 9 (depends on 1) The derivative as claimed in claim 1 wherein Het represents a member selected from the group consisting of pyrrolidine, pyrrole, furan, thiophene, imidazole, pyrazole, isoindole, 2,3-dihydrobenzimidazole-2-one, isoindoline, hydroxyindole, indazole, benzothiophene, benzofuran, benzimidazole, 4,5,6,7-tetrahydrobenzothiophene, carbazole and beta-carboline. ### Claim 10 (depends on 1) The derivative as claimed in claim 1 wherein Het is indole. ### Claim 11 (depends on 1) The derivative as claimed in claim 1 wherein Het is 2,3-dihydroindol. ### Claim 12 (depends on 1) A compound as claimed in claim 1, wherein Het is represented by the formula: ##STR61## wherein R.sup.1 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl-lower alkyl, or an aralkyl; R.sup.2 represents hydrogen, lower alkyl, or aralkyl; and R.sup.3 represents hydrogen, lower alkoxy, nitro, hydroxyl, lower alkoxycarbonyl, or halo; and X represents a single bond. ### Claim 13 (depends on 1) A compound as claimed in claim 1, wherein Het represents a nitrogen-containing heterocyclic group; and X is a single bond connected to the nitrogen atom of the nitrogen-containing heterocyclic ring. ### Claim 14 (depends on 12) A compound as claimed in claim 12, wherein said compound is 5-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole. ### Claim 15 (depends on 1) A compound as claimed in claim 1, wherein said compound is an (R)-compound. ### Claim 16 (depends on 1) A compound as claimed in claim 1, wherein said compound is an (S)-compound. ### Claim 17 (depends on 1) A compound as claimed in claim 1, wherein said compound is 5-[[1-(2-propynyl)indol-3-yl]carbonyl]-4,5,6,7-tetrahydrobenzimidazole. ### Claim 18 (depends on 1) A compound as claimed in claim 1, wherein said compound is 5-[(2,3-dihydroindol-1-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole. ### Claim 19 (depends on 1) A compound as claimed in claim 1, wherein said compound is 1-[(4,5,6,7-tetrahydrobenzimidazole-5-Yl)carbonyl]-2,3-dihydrobenzimidazol -2-one. ### Claim 20 (depends on 1) A compound as claimed in claim 1, wherein said compound is 5-[(2-benzylindol-3-yl)-carbonyl]-4,5,6,7-tetrahydrobenzimidazole. ### Claim 21 (depends on 1) A compound as claimed in claim 1, wherein said compound is 5-[(1-n-butylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole. ### Claim 22 (depends on 1) A compound as claimed in claim 1, wherein said compound is 5-[(1-cyclohexylmethylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole ### Claim 23 (depends on 1) A compound as claimed in claim 1, wherein said compound is 5-[1-benzylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole. ### Claim 24 (depends on 1) A compound as claimed in claim 1, wherein said compound is N-(pyridin-3-yl)-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide. ### Claim 25 (depends on 1) A compound as claimed in claim 1, wherein said compound is N-(5,6-dihydro-4H-cyclopentathiazol-2-yl)-4,5,6,7-tetrahydrobenzimidazole- 5-carboxamide. ### Claim 26 A pharmaceutical composition containing a tetrahydrobenzimidazole derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof: ##STR62## wherein Het represents a member selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, pyrrole, furan thiophene, imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, 4H-cyclopentathiazole, indole, isoindole, 2,3-dihydroindole (indoline), isoindoline, hydroxyindole, indazole, indolizine, benzothiophene, benzofuran, benzothiazole, benzimidazole, benzoxazole, 4,5,6,7-tetrahydrobenzothiophene, 2,3,-dihydrobenzimidazol-2-one, quinoline, isoquinoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 1,4-benzoxazine, phenothiazine, carbazole and .beta.-carboline, and wherein Het may be substituted with 1 to 3 substituents selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl lower alkyl aralkyl, lower alkoxy, nitro, hydroxyl, lower alkoxycarbonyl, and halo; and X represents a single bond or --NH-- which is bonded to the carbon atom or nitrogen atom of the heterocyclic ring, and a pharmaceutically acceptable carrier. ### Claim 27 (depends on 26) A pharmaceutical composition as claimed in claim 26, wherein said composition is a 5HT.sub.3 -antagonist. ### Claim 28 (depends on 26) A pharmaceutical composition as claimed in claim 26, wherein said composition is a treating agent for gastrointestinal disorders. ### Claim 29 (depends on 26) A pharmaceutical composition as claimed in claim 26, wherein said gastrointestinal disorders are anaphylactic intestinal syndrome. ### Claim 30 (depends on 26) A pharmaceutical composition as claimed in claim 26, wherein said composition is a treating agent for nausea and/or vomiting induced by chemotherapy or radiation. ### Claim 31 (depends on 26) A pharmaceutical composition as claimed in claim 26, wherein said composition is a treating agent for migraine, cluster headache and trigeminal neuralgia. ### Claim 32 (depends on 26) A pharmaceutical composition as claimed in claim 26, wherein said composition is a treating agent for anxiety and psychotic disorders.